CZ302786B6 - Anhydrous crystalline tiotropium bromide, process for its preparation and its use for the preparation of a medicament used for the treatment of asthma - Google Patents

Abstract

In the present invention, there is disclosed anhydrous crystalline tiotropium bromide characterized by a monoclinic elementary cell determined by X-ray structural analysis at wavelength {lambda} = 1.54178 A of monochromatic copper {kappa}{alpha}-radiation) with the current intensity of 100 mA and voltage of 50 kV and with the following lattice parameters a=10.4336(2) . 10e-10 m, b=11,3297 (3) . 10e-10 m, c=17,6332 (4) . 10e-10 m, {alpha}=90 degrees, {beta}=105,158 (2) degrees and {gamma}=90 degrees (cell volume = (2011,89 . 10e-10 m)e3). There is also disclosed a process for preparing the above-described anhydrous crystalline tiotropium bromide wherein the preparation process thereof is characterized by drying tiotropium bromide monohydrate at a temperature higher than 50 degC, preferably at a temperature ranging from 60 to 100 degC under reduced pressure. The obtained product can then be used for the preparation of a medicament intended particularly for the treatment of asthma or obstructive pulmonary disease.

Description

Technical field

The invention relates to crystalline (Ia ₁ 2p, 4p, 5a.7p> -7 [(hydroxy-di-2-thienylacetyl) oxy] -9,9-dimethyl -3-oxa-9 azoniatncyklo [3,3, l, 0 ² ' ⁴ ] nonane bromide in anhydrous form, a process for its preparation and its use for the manufacture of a medicament, particularly for the manufacture of a medicament having anticholinergic activity.

BACKGROUND OF THE INVENTION

Compound (1α, 2β, 4β, 5α, 7β) -7 - [(hydroxydi-2-thienylacetyl) oxy] -9,9-dimethyl-3-oxa-9-azo15-niatricyclo [3,3,1,0 ^{2 4} ] nonane bromide is also known from European patent application

EP 418 716 A1 and has the following chemical structure of formula I

The compound has valuable pharmacological properties and is known as tiotropium bromide (BA679BR). Tiotropium bromide is a highly effective anticholinergic and can therefore be used in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

Tiotropium bromide is preferably administered by the inhalatory route. In this case, suitable inhalation powders can be used which are filled into suitable capsules (inhalers) and delivered by means of corresponding powder inhalers. Alternatively, inhalative use may also be by application of suitable inhalation aerosols. They also include powdered inhalation aerosols which contain, for example, HFA134a, HFA227 or a mixture thereof as propellant.

The correct manufacture of the above compositions useful for inhaled administration of the active ingredient is based on various parameters that are associated with the nature of the active ingredient. For drugs which are used as tiotropium bromide in the form of inhalable powders or inhalation aerosols, a crystalline active substance in milled (micronized) form is used to manufacture the formulation. Since the same crystalline modification of the active substance must always be ensured for the pharmaceutical quality of the pharmaceutical formulation, increased demands are therefore placed on the stability and properties of the crystalline active substance. It is particularly desirable to prepare the active ingredient in the form of a uniformly and clearly defined crystal modification. It is furthermore particularly desirable to prepare the active ingredient in crystalline form which does not tend to form polymorphic forms.

In addition to the above requirements, it is generally contemplated that any change in the solid state of a drug that can improve its physical and chemical stability over less stable forms of the same drug provides a significant advantage.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide a new, stable, crystalline form of the tiotropium bromide compound which meets the above-mentioned high requirements which need to be directed to the drug substance.

It has been found that thiotropium bromide, depending on the choice of conditions that can be used in the purification of the crude product obtained by the technical process, is produced in various crystal modifications.

It has been found that these various modifications can be specifically obtained by selecting the solvent used for crystallization and by selecting the process conditions selected in the crystallization process.

The present invention is based on an anhydrous, crystalline tiotropiumbromide having a monoclinic elemental cell, as determined by X-ray structure analysis at a wavelength of λ = 1.54178 A of monochromatic copper Ka at 100 mA and a voltage of 50 kV, with grid parameters a = 10.4336 (2). 10 ^J m, b = 11.3297 (3). 10 ^{, u} m, c = 17.6332 (4). 10 ^µl m, α = 90 °, β = 105,158 (2) ° and γ ^_ 90 ° (cell volume = (2011,89. 10 ^l ° m) ³ ).

Another aspect of the present invention relates to a process for producing a crystalline form of anhydrous tiotropium bromide. This production method is characterized in that tiotropium bromide, which is obtained, for example, according to the process disclosed in EP 418 716 A1, is absorbed in water, the resulting mixture is heated and subsequently crystallized tiotropium bromide hydrate with slow cooling. Anhydrous, crystalline tiotropium bromide can be obtained from the crystalline tiotropium bromide monohydrate thus obtained.

The present invention further relates to the crystalline, anhydrous tiotropium bromide obtained by the above process.

One aspect of the present invention relates to a process for producing crystalline, anhydrous tiotropium bromide starting from crystalline tiotropium bromide monohydrate, which is described in more detail below.

For the production of crystalline monohydrate, tiotropium bromide, which is obtained, for example, according to the process disclosed in EP 418 716 A1, must be absorbed in water, heated, activated charcoal cleaned and slowly allowed to crystallize tiotropium bromide monohydrate after slow cooling. From this crystallizate with gentle heating at more than 50 ° C, preferably at 60 to 100 ° C, particularly preferably at 70 to 100 ° C, under reduced pressure, preferably under high vacuum, for 10 minutes to 24 hours, preferably 20 minutes to 12 hours, the anhydrous form is obtained.

According to the invention, preferably as described above, the solvent is mixed in a reaction vessel of suitable dimensions with tiotropium bromide, which is obtained, for example, according to the process disclosed in EP 418 716 A1.

0.4 to 1.5 kg, preferably 0.6 to 1 kg, particularly preferably ca. 0.8 kg of water as solvent.

The resulting mixture is heated with stirring, preferably to more than 50 ° C, particularly preferably to more than 60 ° C. The maximum selectable temperature is determined by the boiling point of the solvent used - water. Preferably, the mixture is heated between 80 and 90 ° C.

To this solution is added activated carbon, dry or moistened with water. Preferably 10 to 50 g, more preferably 15 to 35 g, most preferably about g of activated carbon are used per mole of tiotropium bromide used. Optionally, the activated carbon is dissolved in a solution containing tiotropium bromide in water prior to introduction. 70 to 200 g, preferably 100 to 160 g, particularly preferably ca. 135 g of water. If the activated carbon is first dissolved in water before being introduced into the solution containing tiotropium bromide, it is recommended to subsequently flush with the same amount of water.

At constant temperature, after the addition of activated carbon, the mixture is further stirred for 5 to 60 minutes, preferably 10 to 30 minutes, particularly preferably about 15 minutes, and the resulting mixture is filtered to remove the activated carbon. The filter is then rinsed with water. In this case, 140 to 400 g, preferably 200 to 320 g, most preferably ca. 270 g of water.

The filtrate is then slowly cooled, preferably to a temperature of 20-25 ° C. The cooling is preferably carried out at a cooling rate of 1 to 10 ° C in 10 to 30 minutes, preferably 2 to 8 ° C in 10 to 30 minutes, particularly preferably 3 to 5 ° C in 10 to 20 minutes, most preferably 3 to 5 ° C za ca. 20 minutes. Cooling to 20 to 25 ° C may optionally be followed by further cooling to below 20 ° C, particularly preferably to 10 to 15 ° C.

After cooling, the solution is further stirred for 20 minutes to 3 hours, preferably 40 minutes to 2 hours, particularly preferably about one hour, until complete crystallization.

The resulting crystals are then isolated by filtration or suction filtration. If it is desired to subject the crystals to the next washing step, it is recommended to use water or acetone as the washing solution. Per mole of tiotropium bromide used, 0.1 to 1.0 L, preferably 0.2 to 0.5 L, particularly preferably about 0.3 L of solvent can be used to wash the obtained tiotropium bromide monohydrate crystals. Optionally, the washing step can be performed repeatedly.

The product obtained is dried under vacuum or with heated circulating air to a water content of 2.5 to 4.0%.

From the thus obtained crystalline tiotropium bromide monohydrate with thorough drying at more than 50 ° C, preferably at 60 to 100 ° C, particularly preferably at 70 to 100 ° C, under reduced pressure, preferably under high vacuum, for 15 minutes to 24 hours , preferably 20 minutes to 12 hours, particularly preferably 30 minutes to 6 hours, obtains the anhydrous form. Particularly preferably, reduced pressure means a value of up to 0.005 MPa (5 x 10 ^-2 bar), preferably 0.001 MPa (1 x 10 ^-2 bar), particularly preferably 0.0005 MPa (5 x 10 ³ bar). More preferably, the dehydration to the anhydrate is performed at a pressure of about 0.0001 MPa (1 x 10 ^-3 bar) or less.

Alternatively to the above drying step at elevated temperature under reduced pressure, the anhydrous form may also be prepared by placing crystalline tiotropium bromide monohydrate over a suitable drying agent, preferably over dry silica gel at room temperature for 12 to 96 hours, preferably 18 to 72 hours, particularly preferably at least 24 hours. hours. The anhydrous form thus obtained should be more or less dry-stored, depending on the particle size, in order to preserve the anhydrous state. In the case of anhydrous tiotropium bromide in the form of coarse crystals, which can be produced, for example, by the above process, storage at a relative humidity of <75% (room humidity) is sufficient to obtain the anhydrous state. In the micronized state, a material with a very enlarged surface, moisture uptake can occur even at lower air humidity. In order to obtain the anhydrous form in the micronized state, it is therefore recommended to store the anhydrous form of tiotropium bromide over dried silica gel (until further processing into the desired inhalation powder containing a suitable excipient (eg lactose) in addition to tiotropium bromide.

One aspect of the present invention relates to the crystalline, anhydrous tiotropium bromide obtained by the above process. Furthermore, the present invention relates to the use of crystalline tiotropium bromide monohydrate for producing crystalline tiotropium bromide in anhydrous form.

-3 CZ 302786 B6

Characteristics of crystalline tiotropium bromide monohydrate

Tiotropium bromide monohydrate obtained according to the above procedure, which serves as the starting material for the production of crystalline, anhydrous tiotropium bromide, was subjected to DSC (Differential Scanning Calorimetry). The DSC diagram has two characteristic signals.

The first, relatively broad, endothermic signal between 50 and 120 ° C is derived from the dehydration of tiotropium bromide monohydrate to the anhydrous form. A second, relatively sharp, endothermic maximum at 23 ± 5 ° C is assigned to the melting of the substance to form decomposition. These data were obtained with the Mettler DSC 821 and evaluated using a Mettler-Software-STAR Pack. Data were plotted at a heating rate of 10 K / min.

Since tiotropium bromide monohydrate melts on decomposition (= incongruent melting), the observed melting point depends very much on the heating rate. At a low heating rate, the melting / decomposition of attention 15 is at significantly lower temperatures, such as at a heating rate of 3 K / min at

220-5 ° C. In addition, it may occur that the melting peak breaks down. The split is stronger the lower the heating rate in the DSC experiment.

The tiotropium bromide monohydrate obtained according to the above process, which serves as a starting material for the production of the crystalline, anhydrous tiotropium bromide of the invention, was characterized by IR-spectroscopy. Data were plotted using a Nicolet FTIR spectrometer and evaluated using the Nicolet software package OMNC, version 3.1, Measurement performed

2.5 μιηοΙ tiotropium bromide monohydrate in 300 mg KBr. Table 1 contains some of the essential bands of the IR spectrum.

Table 1: Assignment of specific belts

Wavelength (cm-1) Assignment Vibration type 3570,3410 OH Line vibration 3105 Acres! C-H Line vibration 1730 what Line vibration 1260 C-O epoxide Line vibration 1035 Esther C-OC Line vibration 720 Thiofen Circular oscillation

The tiotropium bromide monohydrate obtained according to the above process, which serves as a starting material for the production of the crystalline, anhydrous tiotropium bromide of the invention, was characterized by X-ray structure analysis. X-ray diffraction measurements were performed on an AFC7R 4-Kreisdiffractometer (Rigaku) using monochromatic copper Ka. Structure detection and crystal structure refinement were performed using direct methods (Program SHELXS86) and refining FMLQ (Program TeXsan). Experimental details of the crystalline structure, structure detection and structure refinement are given in Table 45 ce2.

-4GB 302786 B6

Table 2: Experimental data for structural analysis of tiotropium bromide monohydrate

A. Crystal Data Empirical Formula Weight by Formula Crystal Color and Shape Crystal Dimensions Crystal System Grid Type Spatial Group Grid Constants [C | ₉ H ₂₂ NO ₄ S _{2] 2} O Br.H

472.43 + 18.00 colorless, prismatic

0.2 x 0.3 x 0.3 mm monoclinic primitive

P2, / to = 18,0774.10 '' ° mb = 11.9711.10 ¹⁰ mc = 9.9321.10 '° m P = 102.691 °

V = (20.96.96.10 &quot; m) ³

Units of formula per unit cell 4

B.

Measurement of intensity

Diffractometer

X-ray generator Wavelength Current, voltage Angle too-off Crystal mounting Crystal-detector distance Detector opening Temperature

Determination of grid constants Scan type 2Θ max Measurement \ T, _Í..L.1Z__

ACZdVIMV 1V1IVAV

Proofreading

Rigaku AFC7R

Rigaku RU200 λ - 1.54178. 10 “ ^1ϋ m (monochromatic copper radiation Ka) 100 mA, 50 kV 6 ° water-saturated capillary

235 mm

3.0 mm vertical and horizontal ° C reflection (50.8 ° <2Θ <56.2 °)

Θ-2Θ

120 °

5193

7TO1 nncn

Lorentz polarization

Absorption (Transmission Factors 0.65 to 1.00)

Crystal decay 10.47% waste

C. Refinement

Reflection (I> 3σ1) 1978

Variable 254

Reflection ratio / parameter 7.8 R-values: R, R _w 0.062, 0.066

-5 CZ 302786 B6

X-ray structure analysis showed that crystalline tiotropium bromide monohydrate has a single monoclinic crystalline cell with the following dimensions:

a - 18.0777.10 ^{1 (1} m, b = 1 1.971 1.10 ¹⁰ mc = 9.9321.10 ^{1 (1} m, β - 102.691 °, V - (2096.96.10 m) ³

The atomic coordinates shown in Table 3 were determined by the above-mentioned X-ray structure analysis.

O

Table 3: Coordinates

Atom X y of u (eq.) Br (1) 0.63938 (7) 0.0490 (1) 0.2651 (1) 0.0696 (4) S (1) 0.2807 (2) 0.8774 (3) 0.1219 (3) 0.086 (1) S (2) 0.4555 (3) 0.6370 (4) 0.4214 (5) 0.141 (2) 0 (2) 0.2185 (4) 0.7372 (6) 0.4365 (8) 0.079 (3) 0 (2) 0.3162 (4) 0.6363 (8) 0.5349 (9) 0.106 (3) 0 (2) 0.3188 (4) 0.9012 (5) 0.4097 (6) 0.058 (2) 0 (3) 0.0416 (4) 0.9429 (6) 0.3390 (8) 0.085 (3) 0 (5) 0.8185 (5) 0.0005 (8) 0.2629 (9) 0.106 (3) N (1) 0.0111 (3) 0.7607 (6) 0.4752 (7) 0.052 (2) NO. 1) 0.2895 (5) 0.7107 (9) 0.4632 (9) 0.048 (3) C (2) 0.3330 (5) 0.7876 (8) 0.3826 (8) 0.048 (3) C (3) 0.3004 (5) 0.7672 (8) 0.2296 (8) 0.046 (3) C (4) 0.4173 (5) 0.7650 (8) 0.4148 (8) 0.052 (3) C (5) 0.1635 (5) 0.6746 (9) 0.497 (1) 0.062 (3) C (6) 0.1435 (5) 0.7488 (9) 0.6085 (9) 0.057 (3) C (7) 0.0989 (6) 0.6415 (8) 0.378 (1) 0.059 (3) C (8) 0.0382 (5) 0.7325 (9) 0.3439 (9) 0.056 (3) C (9) 0.0761 (6) 0.840 (1) 0.315 (1) 0.064 (3) C (10) 0.1014 (6) 0.8974) 8) 0.443 (1) 0.060 (3)

-6 CZ 302786 B6

Continuation of Table 3: Coordinates

Atom X IN of u (eq.) C (11) 0.0785 (5) 0.8286 (8) 0.5540 (9) 0.053 (3) C (12) -0.0632 (6) 0.826 (1) 0.444 (1) 0.086 (4) C (13) -0.0063 (6) 0.6595 (9) 0.554 (1) 0.062 (3) C (14) 0.4747 (4) 0.8652 (9) 0.430 (1) 0.030 (2) C (15) 0.2839 (5) 0.6644 (9) 0.1629 (9) 0.055 (3) C (16) 0.528 (2) 0.818 (2) 0.445 (2) 0,22 mm (1) C (17) 0.5445 (5) 0.702 (2) 0.441 (1) 0.144 (6) C (18) 0.2552 (6) 0.684 (1) 0.019 mm (1) 0.079 (4) C (19) 0.2507 (6) 0.792 (1) -0.016 (1) 0.080 (4) H (1) -0.0767 0.8453 0.5286 0,102 H (2) -0.0572 0.8919 0.3949 0,102 H (3) -0.1021 0.7810 0.3906 0,102 H (4) -0.0210 0.6826 0.6359 0,073 H (5) -0.0463 0.6178 0.4982 0,073 H (6) 0,0377 0.6134 0.5781 0,073 H (7) 0.1300 0.7026 0.6770 0,069 H (8) 0.1873 0.7915 0.6490 0,069 H (9) 0,1190 0.6284 0.2985 0,069 H (10) 0,0762 0.5750 0.4016 0,069 H <11) 0.1873 0.6082 0.5393 0,073 H (12) -0.0025 0.7116 0.2699 0,066 H (13) 0.1084 0.8383 0.2506 0,075 H (14) 0.1498 0.9329 0.4626 0.071

-7EN 302786 B6

Continuation of Table 3: Coordinates

Atom X IN of uíekv. H (15) 0,0658 0.8734 0.6250 0,063 H (16) 0.2906 0.5927 0.2065 0,065 H (17) 0.2406 0.6258 -0.0469 0,094 H (18) 0.2328 0.8191 -0.1075 0,097 H (19) 0.4649 0.9443 0.4254 0,037 H (20) 0.5729 0.8656 0.4660 0.268 H (21) 0.5930 0.6651 0.4477 0.165 H (22) 0.8192 -0.0610 0.1619 0,084 H (23) 0.7603 0.0105 0.2412 0,084

x, y, z: fractional coordinates;

U (eq.) Mean quadratic amplitude of atomic motion in a crystal;

io Characteristics of crystalline, anhydrous tiotropium bromide

As mentioned above, the crystalline anhydrous tiotropium bromide of the invention is available from the starting crystalline tiotropium bromide monohydrate.

The crystalline structure of anhydrous tiotropium bromide was determined by the appearance of high resolution X-ray powder analysis (synchrotron radiation) by adjusting the actual space by so-called "simulated annealing". Subsequent Rietveld analysis was performed to refine the structural parameters. Table 4 contains the obtained experimental data of crystalline, anhydrous tiotropium bromide.

Table 4: Experimental data of crystal structure analysis of tiotropium bromide (anhydrous)

Formula C, ₉ H ₂₂ NO ₄ S ₂ Br Temperature [° C] 25 Molecular weight [g / mol] 472.4 Spatial group P2je and [A] 10.4336 (2) b [A] 11.6332 (4) c [A] 17.6332 (4) β [Α] 105,158 (1) in [A ³ ] 201 1.89 (8) OF 4

recalculated density [g / cm ³ ] 1.56

2Θ (range) [°] 2,0-20

Interval [° 2Θ] 0.003

Numeric time / division [sec] 3

Wavelength []] 0.7000

Accordingly, the present invention relates to crystalline, anhydrous tiotropium bromide, which is characterized by an elemental cell and - 10.4336. 10 ^'10 b = 11.3297. 10 ' ^{, 0} mc = 17.6332. 10 ' ¹ ° ma = 90 °, β - 105,158 (2) ° and γ = 90 °, (cell volume - 2011,89 (8). IC ¹⁰ ' ¹⁰ m

The crystal structure of the anhydrous form of tiotropium bromide can be described as the layer structure. Bromide ions are located between the tiotropium layers.

To explain the crystalline, anhydrous tiotropium bromide structure at room temperature, a high resolution X-ray powder diagram was generated at room temperature at the National Synchrotron Source (Brookhaven National Laboratory, USA) at X3B1 (λ = 0.700.10 ¹⁰ m). For this experiment, a sample of crystalline tiotropium bromide monohydrate was placed in a 0.7 mm diameter quartz glass capillary. Water was removed from the furnace by heating to 80 ° C under reduced pressure.

The structure was determined by so-called "simulated tempering". The programmed DASH package from the Cambridge Ciystallographic Data Center (CCDC, Cambridge, United Kingdom) was used.

Table 5 contains the atomic coordinates obtained for crystalline, anhydrous tiotropium bromide.

Table 5: Coordinates

Atom X IN of U „O S1 1.0951 (8) 0.3648 (8) 0.8189 (5) 0.075 (9) S1 0.9143 (9) 0.1374 (8) 0.9856 (5) 0.075 (9) 0 0.6852 (13) 0.2339 (6) 0.7369 (6) 0.075 (9) 01 0.7389 (15) 0.0898 (9) 0.8234 (6) 0.075 (9) 02 / 0.8211 (10) 0.3897 (17) 0.8277 (7) 0.075 (9) 03 / 0.4975 (17) 0.4816 (9) 0.6011 (7) 0.075 (9)

-9 GB 302786 B6

Continuation of Table 5

Atom X IN OF u, _so N 0.4025 (10) 0.2781 (8) 0.5511 (5) 0.075 (9) C 0.7509 (8) 0.1885 (6) 0.8038 (5) 0.075 (9) NO. 1 0.8593 (7) 0.2788 (5) 0.8495 (4) 0.075 (9) C2 0.9924 (9) 0.2533 (6) 0.8225 (6) 0.075 (9) C3 0.8884 (9) 0.2664 (7) 0.9382 (4) 0.075 (9) C4 0.5848 (12) 0.1596 (8) 0.6753 (8) 0.075 (9) C5 0.4544 (13) 0.1929 (14) 0.6809 (8) 0.075 (9) C6 0.6156 (13) 0.1810 (13) 0.5973 (9) 0.075 (9) C7 0.5493 (11) 0.2881 (11) 0.5578 (6) 0.075 (9) C8 0.5869 (12) 0.3832 (11) 0.6092 (7) 0.075 (9) C9 0.4947 (13) 0.3902 (10) 0.6575 (6) 0.075 (9) C10 0.4004 (10) 0.2998 (11) 0.6332 (6) 0.075 (9) C11 0.3220 (13) 0.3670 (13) 0.4935 (6) 0.075 (9) C12 0.3450 (19) 0.1643 (26) 0.5211 (11) 0.075 (9) C13 0.9184 (16) 0.3808 (9) 0.9920 (6) 0.075 (9) C14 1.0313 (16) 0.1552 (15) 0.8011 (15) 0.075 (9) C15 0.9515 (17) 0.3374 (10) 0.0501 (6) 0.075 (9) C16 0.9756 (18) 0.2190 (11) 1.0742 (5) 0.075 (9) C17 1.1483 (22) 0.1762 (18) 0.7718 (24) 0.075 (9) C18 1.1860 (16) 0.2800 (15) 0.7768 (19) 0.075 (9) BR 0.4597 (4) 0.8200 (15) 0.61902 (25) 0.042 (9) above table means values "U _1S0 " isotropic temperature factors For example

- 10-crystal X-ray structure analysis corresponds to u (eq) values.

Table 6 contains the reflexes (indices - h, k, I) of the powder plot obtained for crystalline, anhydrous tiotropium bromide.

Table 6: Experimental data on crystal structure analysis of anhydrous bromide bromide

C. h k I 2 © _O bs. 20 _C ale. 20 _o bs. 20caic. 1 1 0 0 8,762 8,769 -0,007 2 0 1 1 9,368 9,369 -0.001 3 -1 0 2 11,730 11,725 0.005 4 0 1 2 12,997 13,004 -0,007 5 -1 1 2 14,085 14,094 -0.009 6 1 0 2 15,271 15,275 -0.004 7 0 0 3 15,620 15,616 0.004 8 0 2 1 16,475 16,475 0.0 9 1 1 2 17,165 17,170 -0.005 10 2 0 0 17,588 17,591 -0.003 11 -1 2 1 18,009 18,035 -0.026 12 1 2 1 19,336 19,328 0.008 13 -2 1 2 19,596 19,600 -0.004 14 -1 0 4 20,417 20,422 -0.005 15 Dec 0 0 4 20,865 20,872 -0,007 16 2 1 1 21,150 21,145 0.005 17 -2 1 3 21,759 21,754 0.005 18 0 2 3 22,167 22,160 0.007

Table 6

h to AND 2 © _both . © catc. 2 © obs. '2 © _ca ic -1 2 3 22,289 22,288 0.001 2 0 2 22,735 22,724 0.011 -2 2 1 23,163 23,159 0.004 -2 0 4 23,567 23,575 -0.008 2 1 2 24,081 24,058 0,023 1 0 4 24,746 24,739 0.007 -1 3 1 25,220 25,221 -0.001 1 2 3 25,359 25,365 -0.006 0 3 2 25,790 25,783 0.007 1 1 4 25,978 25,975 0.003 0 2 4 26,183 26,179 0.004 -1 3 2 26,383 26,365 0.018 -1 1 5 26,555 26,541 0.014 -3 1 2 27,024 27,021 0.003 3 1 0 27,688 27,680 0.008 -3 1 3 28,221 28,215 0.006 3 0 1 28,377 28,376 0.001 -3 0 4 29,246 29,243 0.003

- 12GB 302786 B6

Continuation of Table 6 No h to 1 2 © obs. - . 20calc. 2 © both. ^- 2 © _ca tc 37 3 1 1 29,459 29,471 -0.012 38 -1 2 5 29,906 29,900 0.006 39 -3 2 1 30,171. 30,165 0.006 40 0 2 5 30,626 30,626 0.0 41 1 1 5 30,871 30,856 0.015 42 0 0 6 31,504 31,532 -0.028 43 2 1 4 31,826 31,847 -0.021 44 -2 1 6 32,888 32,888 0.0 45 1 4 1 33,605 33,615 -0.010 46 3 0 3 34,379 34,377 0.002 47 1 0 6 35,021 35,018 0.003 48 -4 1 1 35,513 35,503 0.01 49 1 1 6 35,934 35,930 0.004 50 -1 1 7 36.544 36 543 0.001 51 -4 1 4 37,257 37,255 0.002 52 -4 2 2 37,933 37,952 -0.019 53 4 1 1 38,258 38,264 -0.006

Another aspect of the present invention relates to the use of crystalline, anhydrous tiotropium bromide as a medicament due to the pharmaceutical activity of the anhydrous form of the invention. The manufacture of a medicament to be administered by the inhalatory route, in particular an inhalation powder containing the anhydrous, crystalline tiotropium bromide described by the present invention, can be carried out in a manner known in the art. Accordingly, reference is made, for example, to the content of DE-A 179 22 07. Accordingly, another aspect of the present invention is directed to an inhalation powder which is characterized by a content of crystalline, anhydrous tiotropium bromide.

Due to the high potency of tiotropium bromide, the aforementioned inhalation powders preferably contain, in addition to the active ingredient, physiologically acceptable excipients. For example, the following physiologically acceptable excipients may be used: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, sucrose, maltose) oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylite), salts ( sodium chloride, sodium carbonate) or mixtures of these excipients with each other. Preferably, mono- or disaccharides are used, with the use of lactose or glucose, particularly but not exclusively, in the form of their hydrates. Lactose, most preferably lactose monohydrate, is used as the adjuvant in particular for the purposes of the invention.

The excipients have a maximum mean particle size of up to 250 µm, preferably 10 to 150 µm, particularly preferably 15 to 80 µm, within the inhalation powders according to the invention, which are characterized by an anhydrous, crystalline tiotropium bromide content. Optionally, finer excipient fractions with an average particle size of 1 to 9 µm may be suitable for the above excipients. The latter finer excipients are also selected from the abovementioned classes of useful excipients.

Preferred inhalation powders comprising the tiotropium bromide anhydrate according to the invention are characterized in that the excipient consists of a coarser excipient with an average particle size of 17 to 50 µm, particularly preferably 20 to 30 µm and finer excipients with an average particle size of 2 to 8 µm. particularly preferably 3 to 7 µm. As used herein, the mean particle size refers to a 50% value of the volume of distribution measured by a laser diffractometer according to the dry dispersion method. Preferred are inhalable powders in which the proportion of finer excipient in the total amount of excipient is 3 to 15%, particularly preferably 5 to 10%.

A possible method of making this preferred inhalation powder according to the invention is described in more detail below.

After the starting materials have been weighed, the auxiliary substances are first prepared from the defined fractions of the coarser auxiliary and the finer auxiliary. Subsequently, the inhalation powder according to the invention is prepared from a mixture of excipients and active ingredient. If it is to be administered by means of inhalers in suitable inhalers, the production of inhalable powders is followed by the production of powder capsules.

The preparation of the inhalable powders according to the invention is carried out by mixing coarser proportions of excipients with finer proportions of excipients and subsequently mixing the mixture of excipients thus obtained with the active ingredient.

In the preparation of the excipient mixtures, the coarser and finer excipient proportions are fed into a suitable mixing vessel. The addition of both components is preferably carried out with a sieve granulator having a mesh size of 0.1 to 2 mm, particularly preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm. Preferably, a coarser excipient is introduced into the mixing vessel and subsequently a finer proportion of excipient is introduced. Preferably, in this mixing process, the two components are added in portions, one portion of the coarser excipient first being introduced and then a finer and coarser excipient is added alternately. Particularly advantageous in the production of excipient mixtures is the alternate pouring of the two components over the layers. Preferably, the two components are poured in alternation of 15 to 45, particularly preferably of 20 to 40 layers. The mixing of both excipients can take place already during the addition of both components. Preferably, however, it is only mixed after the two components have been sieved in layers.

- 14GB 302786 B6

After the preparation of the excipient mixture, the mixture and the active substance are introduced into a suitable mixing vessel. The active ingredient used has a mean particle size of 0.5 to 10 µm, preferably 1 to 6 µm, particularly preferably 2 to 5 µm. The addition of the two components is preferably carried out with a sieve granulator having a mesh size of 0.1 to 2 mm, particularly preferably 0.3 to 1 mm, most preferably 0.3 to 0.6 mm. Preferably, the excipient mixture is introduced and the active ingredient is subsequently introduced into the mixing vessel. Advantageously, the two components are added in portions. It is particularly advantageous to alternately admix the two components in layers in the preparation of the excipient mixture. Preferably, the two components are sieved in alternation of 25 to 65, more preferably 30 to 60 layers. The mixing of the excipient mixture with the active substance can already take place during the addition of both components. Preferably, however, it is only mixed after the two components have been layered.

The powder mixture thus obtained can be sieved again one or more times with a sieve granulator and subsequently subjected to further mixing.

The inhalable powders obtained according to the above method preferably contain about 0.001 to 2% tiotropium in admixture with a physiologically acceptable excipient. Inhalable powders containing 0.04 to 0.8% tiotropium in admixture with a physiologically acceptable excipient are preferred, characterized in that the excipient consists of a mixture of a coarser excipient with an average particle size of 15 to 80 µm and a finer excipient. a mean particle size of 1 to 9 µm, the proportion of the finer excipient in the total amount of excipient being 1 to 20%.

Preferred according to the invention are inhalation powders which contain 0.08 to 0.64%, particularly preferably 0.16 to 0.4% tiotropium.

When anhydrous, crystalline tiotropium bromide is used in the above-mentioned inhalation powders, these powder mixtures preferably contain 0.0012 to 2.41% tiotropium bromide anhydrate. Correspondingly preferred are inhalation powders containing 0.048 to 0.96% tiotropium bromide anhydrate. Inhalation powders which contain 0.096 to 0.77%, particularly preferably 0.19 to 0.48% of tiotropium bromide anhydrate are of particular interest according to the invention.

The percentages given in the present invention are still percentages by weight.

Alternatively, as well as a preferred embodiment of the manufacture of inhalable powders containing tiotropium bromide anhydrate may further proceed by starting from inhalation powders which have been formulated on the basis of crystalline tiotropium bromide monohydrate. These comprise 0.0012 to 2.5%, preferably 0.05 to 1%, preferably 0.1 to 0.8%, particularly preferably 0.2 to 0.5% of crystalline tiotropium bromide monohydrate and are preferably available analogously to the above. way. These inhalable powders containing crystalline tiotropium bromide monohydrate can be dried at a temperature greater than 60 ° C, preferably 65-100 ° C, particularly preferably at 70-100 ° C, under reduced pressure, preferably under high vacuum, for 15 minutes up to 24 hours, preferably 20 minutes to 12 hours, particularly preferably 30 minutes to 6 hours, to form inhalation powders containing the tiotropium bromide anhydrate of the invention, either before filling the corresponding inhalation capsules or preferably after filling into the corresponding inhalation capsules. Particularly preferably, the reduced pressure means a value to 0.005 MPa (5 x 10 ^-2 bar), preferably 0.001 MPa (1 x 10 ^-2 bar), more preferably 0.0005 MPa (5 x 10 ^"3 bar). More preferably, the above dehydration to the anhydrate is performed at a pressure of about 0.0001 MPa (1 x 10 ^-3 bar) or less.

Due to the anticholinergic effect of tiotropium bromide, another aspect of the present invention is directed to the use of crystalline, anhydrous tiotropium bromide for the manufacture of a medicament for the treatment of diseases, where administration of an anticholinergic can develop therapeutic use. Preferably, the corresponding use is in the manufacture of a medicament for the treatment of asthma or COPD.

- 15 GB 302786 B6

The following synthesis example is intended to illustrate exemplary methods of making anhydrous, crystalline tiotropium bromide. This is to be understood as meaning only the possible processes mentioned, for example, without limiting the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Synthesis example io

A) Production of crystalline tiotropium bromide monohydrate

In a suitable reaction vessel, 15.0 kg of tiotropium bromide is introduced into 25.7 kg of water. The mixture was heated to 80-90 ° C and stirred at the same temperature until a clear t5 solution was formed. Water-moistened activated carbon (0.8 kg) was washed in 4.4 kg of water, this mixture was dissolved in a solution containing tiotropium bromide and then washed with 4.3 kg of water. The mixture thus obtained is stirred for at least 15 minutes at a temperature of 80 to 90 ° C and then filtered by means of a heated filter into a device preheated to a jacket temperature of 70 ° C. The filter is then washed with 8.6 kg of water. Cool the contents of the apparatus at a rate of 3 to 5 ° C in 20 minutes to a temperature of 20 to 25 ° C. By cooling with cold water, the apparatus is further cooled to a temperature of 10 to 15 ° C and crystallization is complete at least for one hour followed by stirring. The crystallizate is isolated by suction, the isolated crystal slurry is washed with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C). The obtained crystals were dried at 25 ° C for 2 hours in a stream of nitrogen.

Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory)

B) Production of crystalline anhydrous tiotropium bromide

From the crystalline tiotropium bromide monohydrate obtained by the method described above, baking is dried at 80 to 100 ° C under reduced pressure, preferably under high vacuum (at a pressure of about 0.0001 MPa (1 x 10 ^-3 bar) or less) for a period of time. at least 30 minutes to produce the anhydrous mold. Alternatively to the drying step at 80 to 100 ° C under vacuum, the anhydrous form can also be produced by storing over dried silica gel at room temperature for at least 24 hours.

Claims (11)

PATENT CLAIMS Anhydrous, crystalline tiotropium bromide, characterized in that it has a monoclinic elemental cell, as determined by X-ray structure analysis at a wavelength λ = 1.54178 Å of monochromatic copper radiation Ka at a current of 100 mA and a voltage of 50 kV, with a-10 4336 (1). 10 ¹⁰ m, b '11.3297 (3). 10 ¹⁰ m, c = 17.6332 (4). 10 10 ¹⁰ m, α = 90 °, β = 45 105,158 (2) ° and γ - 90 ° (cell volume = (2011,89. 10 ¹⁰ m) ³ ). Process for the production of crystalline anhydrous tiotropium bromide according to claim 1, characterized in that the tiotropium bromide monohydrate is dried at a temperature above 50 ° C, preferably at a temperature of 60 to 100 ° C under reduced pressure. Method according to claim 2, characterized in that the drying takes place for 15 minutes to 24 hours. - 16GB 302786 B6 The method of claim 2, wherein the crystalline anhydrous tiotropium bromide is produced by depositing crystalline tiotropium bromide monohydrate over a suitable drying agent for a period of 12 to 96 hours. 5. The process for producing crystalline anhydrous tiotropium bromide according to claim 2, wherein the starting material is crystalline tiotropium bromide monohydrate. 6. A medicament comprising the crystalline anhydrous tiotropium bromide of claim 1. io Medicament according to claim 6, characterized in that it is an inhalation powder. Inhalable powder as claimed in claim 7, characterized in that it contains, in admixture with a physiologically acceptable excipient, the crystalline anhydrous tiotropium bromide according to claim 1. Inhalable powder according to claim 8, characterized in that the excipient is selected from the group consisting of glucose and lactose. 20 May The use of the crystalline anhydrous tiotropium bromide of claim 1 for the manufacture of a medicament for the treatment of diseases in which administration of an anticholinergic may cause a therapeutic improvement. The use of claim 10, wherein the disease is asthma or chronic obstructive pulmonary disease.